There is a desperate need for new means to diagnose and treat most human diseases. Extracellular small RNAs provide great promise. In particular, recent findings provide strong evidence for their utility as biomarkers. Furthermore, very recent work shows functional roles for at least a subset of the extracellular small RNAs, which provides an opportunity for their manipulation in the treatment of disease. However, as the field is so recent with only anecdotal evidence in limited systems, there remains a fundamental gap in our knowledge of how wide spread the phenomenon of functional extracellular small RNAs really is and how can its potential be fully realized. This U19 Center's long-term goal is to uncover paradigms of extracellular small RNA function in health and disease and apply those paradigms to clinically relevant settings including biomarker discovery and therapeutic intervention. Members of the Center already have a significant track record in these areas. The objective here is to delve into the mechanism and role of small non-coding RNA secretion looking for unifying themes across tissues including the immune system, the liver, the prostate, and neural system and across species from C.elegans to mouse to human. The overarching hypothesis is that extracellular small RNAs represents a heterogeneous landscape that ranges from miRNA dumping to active signaling, and which can be differentiated based on the selectivity and form of their release into body fluids. The Center proposes to tackle this hypothesis by integrating the efforts of six principle investigators with expertise in differet types of small non-coding RNAs, in multiple model organisms, in the biochemistry of secretion and metabolism of lipid, and in imaging. The Center will consist of four projects and a scientific core dedicated to the isolation and characterization of lipid-associated and lipid-free forms of extracellular small RNAs. The aims will be to determine the source, the form, the destination, and the function of extracellular small RNAs in four distinct settings: immune stimulation, primary cancer progression, metastatic tumor growth, and olfactory neuron stimulation. Completion of these aims is expected to uncover common paradigms as well as distinct mechanisms reflecting the different drivers across these settings. This U19 Center proposal is highly significant as it will provide a vertical leap in our knowledge of what extracellular small RNAs represent and what their downstream functions are. This knowledge will enable improved insights into how to use extracellular small RNAs to follow disease and how to manipulate their levels in order to treat disease.